published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Medicine / Master / Doctor of Medicine

Cancer is one of the most notorious diseases affecting the human population today with very few effective treatments. Due to the disparate nature of cancers, it is difficult to obtain a treatment that can cure cancer. Thus, there is a large influx of research towards cancer therapies, leading to one of the discovery that cancer cells (tumors) have a low thermotolerance in comparison to normal cells. If the temperature of the cancer cells is increased into the hyperthermia range (~45°C) thermal damage occurs, causing cell death by protein denaturation and membrane disruption. A recent development in this field has been in the photothermal treatment of tumors, which is starting to utilize plasmonic particles to enhance the specificity of the treatment. The plasmonic nanoparticles, specifically gold, can reach the tumor site using passive targeting and when irradiated with a tuned laser will emit heat localized to a small region around the nanoparticle killing the surrounding cancer cells. This process has been shown to reduce tumor size in vivo with gold nanoshells and gold nanorods. However, it has not been shown which particle is better at delivering the heat to the tumor site. Therefore in this study, it will be shown which particle generates the most heat. Solutions of tissue simulating phantom and different concentrations of nanoparticles were irradiated with a laser to measure the increase in temperature. Additionally, simulations were performed using Mie Theory for nanoshells and the Discrete Dipole Approximation for nanorods. Based on the physical parameters of the nanoshells and nanorods used in this experiment, the adjusted absorption cross-section was determined. It was found that nanoshells generated the most amount of heat on a per particle basis, and that it was necessary to have a nanorod concentration of 5.5 times the concentration of nanoshells to generate the same amount of heat as nanoshells. These results were confirmed using Monte Carlo and Finite Difference Modeling of the nanoparticle heating experiments. However, the choice of nanoparticle still depends on the application and the targeting efficiency in vivo. / text

Diagnosis of head and neck squamous cell carcinoma (HNSCC) presents a multifarious problem. Late stage diagnosis, uncertainty regarding appropriate clinical treatment, as well as the high potential for disfigurement and functional loss resulting in diminished quality of life, contributes to anxiety, stress, fear, and uncertainty throughout the cancer treatment experience. This qualitative study sought to explore the cancer treatment experience of adults with newly diagnosed HNSCC, including laryngeal, esophageal, and oral cancers. Study participants were recruited from the University of Kentucky Ear Nose and Throat Clinic in Lexington KY. Participants agreed to be interviewed after receipt of their cancer diagnosis and again after completion of their cancer treatment. Socio-emotional Selectivity Theory, and Leventhal’s Self-Regulation Model provided the theoretical foundation for exploring the ongoing emotional, psychological, and physical aspects of the cancer experience while also recognizing the role of age and time perception. Forty-one patients completed two in depth semi- structured interviews. Transcripts were coded for key themes. Findings indicated that HNSCC in older patients is often preceded by lifelong alcohol, tobacco, and substance use. Despite frequent interaction with health and substance abuse treatment professionals, very few patients had prior knowledge of HNSCC risk or had been screened for these cancers. Experience with addiction treatment programs and perceptions of time seem to influence cancer treatment experience. The following themes were identified: (1) dynamic time perspectives including taking time, making time, junk time and time out; (2) recovery vs. cure from disease; (3) the role of reconciliation, hope, self-inventory, reflection, and spirituality in navigating the cancer experience; (4) the role of healing vs. cure; and (5) patient's moving forward to a life after cancer. Findings from this investigation suggest that patients with a history of lifelong substance use could benefit from earlier detection and improved awareness and knowledge of HNSCC risk. Findings can be applied to improve access to cancer screening through addiction and cessation programs, reduce lags in diagnosis, improve prognosis and contribute to the development of clinical tools. Additionally, the intersection of advancing chronological age, comorbidity, and perception of time warrants further investigation.

Numerical investigations of heat transfer in single and multiple thick-walled pipes and countercurrent pairs are used to deduce relationships between fluid and solid temperatures needed to develop more accurate thermal models of living tissue in the extremities. A structural model of heat transfer in living tissue is developed using currently available anatomical and physiological data for the extremities. In order to improve the heat transfer basis of thermal modeling under in vivo conditions, four heat transfer problems based on structures found in the extremities are solved using in vivo parameters-the thick-walled pipe and countercurrent pair, and the multiple thick-walled pipes and countercurrent pairs-are studied. Low resolution numerical models are devised to approximate the thick-walled pipe and the non-concentric thick-walled countercurrent pair in square geometries. A constant heat transfer coefficient at the fluid-solid interface adequately approximates the fluid and solid temperatures for moderate flow conditions (Peclet number of 10 < °Pe < 1000). In the thick-walled countercurrent pair, countercurrent exchange and fluid-solid thermal interaction are found to act simultaneously, giving rise to imperfect countercurrent exchange. Fluid and solid temperatures in the multiple thick-walled pipes and pairs near the outer boundary resemble those of the single thick-walled pipes and pairs. The countercurrent pairs near the center also exhibit imperfect countercurrent exchange. In cylinders with L* > 1 containing multiple countercurrent pairs, the shapes of the temperature profiles cannot be distinguished from the temperature profile shapes of cylinders containing multiple thick-walled pipes. Fluid and solid temperatures in multiple parallel pipes may be approximated with a field equation which has the same form as the Pennes' bioheat equation. Unlike Pennes' equation, the coefficients for the blood thermal energy term quantify the dependence of the amount of thermal energy transferred between blood and tissue with the geometry of the blood the flow rate through the dimensionless axial length L*, and the dimensionless axial coordinate x* . Comparisons of structural model temperatures with available in vivo temperature studies show that blood and tissue temperatures are consistent with fluid and solid temperatures of either multiple unpaired pipes or multiple countercurrent pairs embedded in a solid cylinder. Further improvements of the basis for in vivo heat transfer modeling are crucially dependent upon more extensive comparison with three-dimensional in vivo studies.

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A transient three-dimensional simulation program was developed to study the effects of scanning speed, scanning pattern, blood perfusion, transducer choice and multiple tilted transducers with overlapping foci during scanned focussed ultrasound hyperthermia. The results showed that (1) the temperature fluctuations increase linearly with decreasing scanning speed, (2) the temperature fluctuations are a weak, increasingly exponential function of the blood perfusion rate, and (3) that the largest temperature fluctuation is always located at the acoustical focal depth on the scan path independently of focal plane depth. Simulations using multiple scan paths showed that relatively uniform average temperature distributions can be achieved at the focal zone as long as the spacing between the concentric scans was not greater than the diameter of the focus of the power field. Finally, the results showed that using multiple tilted transducers with overlapping foci, increased focussing can be obtained at the focal depth.

The synthesis of 7-N-acetyldemethyllavendamycin butyl amide (47), 7-Nacetyldemethyllavendamycin isopropyl amide (48), 7-N-acetyldemethyllavendamycin amide of piperidine (49), 7-N-acetyldemethyllavendamycin amide of pyrrolidine (50), 7N-acetyldemethyllavendamycin amide of morpholine (51), demethyllavendamycin butyl amide (52), demethyllavendamycin amide of pyrrolidine (53), and demethyllavendamycin amide of morpholine (54) are described. Pictet Spengler condesation of 7-acetamido-2formylquinoline-5,8-dione (28) with tryptophan butyl amide (66), tryptophan isopropyl amide (67), tryptophan amide of piperidine (68), tryptophan amide of pyrrolidine (69), and tryptophan amide of morpholine (70) in an anisole - pyridine solution directly afforded the five lavendamycin amides 47-51. Compounds 52, 53, and 54 were obtained by hydrolysis of 47, 50, and 51 with 70% H2SO4-H20 solution.Aldehyde 28 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) yielded 8-hydroxy-2-methyl-5,7 dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with acetic anhydride to yield 5,7-diacetamido-2-methyl-8-acetoxyquinoline (33). Compound 33 was oxidized by potassium dichromate to give 7-acetamido-2-methylquinoline-5,8-dione (27). Treatment of 27 with selenium dioxide in refluxing 1,4-dioxane afforded compound 28.Compounds 66, 67, 68, 69, and 70 were synthesized from compounds 61,62, 63, 64, and 65. These compounds were deprotected with ammonium formate in the presence of 10% Palladium on charcoal in methanol under an argon balloon at atmospheric pressure.Compounds 61, 62, 63, 64, and 65 were obtained from 58 with butylamine, isopropylamine, piperidine, pyrrolidine, and morpholine respectively in the presence of triethylamine under an argon balloon at atmospheric pressure.Compound 58 was synthesized by the reaction of N-carbobenzyloxytryptophan, with N-hydroxy succinimide, in the presence of N-dicyclohexylcarbodimide in dried and distilled dioxane under an argon balloon at atmospheric pressure.The structures of the novel compounds 58, 47, 48, 49, 50, 51, 52, 53, and 54 were confirmed by 1H NMR, IR, EIMS, and HRMS.The structures of protected and deprotected amides 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70 were also confirmed by 1 H NMR and IR spectroscopy. / Department of Chemistry

<p>The prevalence of cancer has increasingly become a significant threat to human health and as such, there exists a strong need for developing novel methods for early detection and effective therapy. Nanotheranostics, a combination of diagnostic and therapeutic functions into a single nanoplatform, has great potential to be used for cancer management by allowing detection, real-time tracking, image-guided therapy and therapeutic response monitoring. Gold nanostars (GNS) with tip-enhanced plasmonics have become one of the most promising platforms for cancer nanotheranostics. This work is aimed at addressing the challenges of sensitive cancer detection, metastasis treatment and recurrence prevention by combining state-of-the-art nanotechnology, molecular imaging and immunotherapy. A multifunctional GNS nanoprobe is developed with capabilities ranging from non-invasive, multi-modality cancer detection using positron emission tomography (PET), magnetic resonance imaging (MRI) and X-ray computed tomography (CT), to intraoperative tumor margin delineation with surface enhanced Raman spectroscopy (SERS) and high-resolution nanoprobe tracking with two-photon photoluminescence (TPL), as well as cancer treatment with photoimmunotherapy. The GNS nanoprobe with PET scans is particularly exceptional in detecting brain malignancies as small as 0.5 mm. To the best of our knowledge, the developed GNS nanoprobe for PET imaging provides the most sensitive means of brain tumor detection reported so far. In addition, the GNS nanoprobe exhibits superior performance as photon-to-heat transducer and can be used for specific photothermal therapy (PTT). More importantly, GNS-mediated PTT combined with checkpoint inhibitor immunotherapy has been found to trigger a memorized immunoresponse to treat cancer metastasis and prevent recurrence in mouse model studies. Furthermore, a 6-month in vivo toxicity study including body weight monitoring, blood chemistry test and histopathology examination demonstrate GNS nanoparticles’ biocompatibility. Therefore, the multifunctional GNS nanoprobe exhibits superior cancer detection and treatment capabilities and has great promise for future clinical translation in cancer management.</p> / Dissertation

Photodynamic therapy (PDT) is a cancer treatment method in which a photosensitizer, light of a particular wavelength, and also oxygen are used to destroy cancerous cells. Cancer cells absorb the photosensitizing agent which is injected into the body, and it is triggered to cause cell destruction upon absorption of light. This occurs because of the excitation of the photosensitizer produces reactive oxygen species that induce a cascade of cellular and molecular events in the body. Photosensitizing agents that can photo-cleave DNA at long wavelengths are highly demanded in PDT, because the long wavelengths of light can penetrate through tissue deeply compared to visible light. While most of the photosensitizers are activated at wavelengths less than 690 nm, penetration of light continues to increase at increasing wavelengths. In this thesis, photosensitizers that can be activated to oxidize DNA with long wavelengths of light will be discussed. Using quinoline cyanine dyes, here we report the first example of DNA photocleavage at a wavelength of light above 800 nm.